Changes in biology of internal fat may be the leading cause of heart failure

Heart failure with preserved ejection fraction (HFpEF) appears to develop as a result of changes in the biology of a person’s internal fat tissue, according to the Adipokine Hypothesis, a new way of understanding how fat may impact the heart.

The hypothesis paper was published today in JACC and is being presented at ESC Congress 2025. The author of the paper is Milton Packer, MD, FACC, Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center at Dallas and Visiting Professor at Imperial College in London.

“Up to now, there has been no unifying hypothesis to explain HFpEF. That has resulted in significant misunderstanding and a lack of direction in both diagnosis and therapy,” Packer said. “This bold new framework helps to identify the true cause of HFpEF in most people. That should make an enormous difference in guiding effective treatments.”

HFpEF is the most common type of heart failure, impacting nearly 4 million people in the United States and 32 million people worldwide. With HFpEF, the heart’s muscle is stiff, and thus, it cannot accommodate the blood it receives. This causes overfilling of the heart and increases in the internal pressures within the heart, leading to shortness of breath during effort. It can also cause fluid buildup in the lungs, abdomen or legs.

It has long been thought that high blood pressure is the leading cause of HFpEF, but that may not be the case. Instead, nearly all patients with HFpEF have significant excess fat tissue that surrounds vital organs, including the heart. However, until now, it has not been understood how this excess internal fat tissue causes heart failure.

This paper introduces the Adipokine Hypothesis, which is a new conceptual framework that explains how excess internal fat tissue contributes directly to the development of HFpEF.

Adipokines are signaling molecules that are released by fat tissue and allow it to communicate with the rest of the body. In a healthy person, adipokines play a nurturing role. They protect the heart and kidneys, helping to reduce stress and inflammation, while maintaining sodium and fluid balance. But when there is excess internal fat, the biology of the fat tissue is transformed. Fat tissue begins to produce and release a different suite of adipokines, and these promote stress, inflammation and scarring in the heart, thus leading to HFpEF.

Experimental studies demonstrate that drugs can alleviate HFpEF, not by targeting the heart, but by acting directly on fat tissue to change its adipokine profile.

The Adipokine Hypothesis points to the importance of using drugs that shrink fat tissue and restore its healthy biology. Many of these drugs are already approved by the FDA for the treatment of HFpEF, but they are not widely prescribed. In addition, GLP-1 receptor agonists—semaglutide and tirzepatide—can exert favorable effects on the release of adipokines.

According to the paper, the term obesity should not be used to identify people with excessive internal fat tissue. Obesity is defined by body mass index, which is heavily influenced by bone and muscle. Instead, the most reliable approach for identifying people with excess internal fat stores is to measure the ratio of waist to height.

Normally, the ratio should be less than 0.5, meaning that the waist is less than half of the height. Nearly all patients with HFpEF have a waist-to-height ratio greater than 0.5, and often greater than 0.6. Such a ratio is clinically important, even when the body mass index does not fulfill criteria for obesity.

“In patients with an elevated waist-to-height ratio, clinicians should be very vigilant to ask patients about potential symptoms of HFpEF,” Packer said. “Many people who are short of breath with walking attribute their symptoms to obesity, when in fact, these symptoms are related to HFpEF and can be effectively treated.”

Thirty-three years ago, Packer proposed a unifying theory to explain heart failure with a reduced ejection fraction, known as the neurohormonal hypothesis. That paper, which was published in JACC, changed how physicians thought about the disorder.

The Adipokine Hypothesis paper in JACC focuses on adipokine proteins. Two additional papers on the role of eicosanoid adipokines in inflammation in HFpEF and on adipoexosomal microRNAs in HFpEF are also being published today in JACC: Heart Failure.